Prostaglandins (PG) E2,E1,6-keto-E1 and D2 at concentrations of 0.15-0.80 microM inhibited by 25% the generation of superoxide anions (O2-) in human polymorphonuclear leukocytes (PMNs) stimulated with formyl-methionyl-leucyl-phenylalanine (FMLP). The potency of that inhibition by either PGD2 or PGE1 was the same when zymosan was used as a stimulator whereas PGE2 and 6-keto-PGE1 were by 13 and 21 times less potent inhibitors of O2-) in zymosan-stimulated as compared to FMLP-activated PMNs. PGF2 alpha inhibited the generation of O2- by activated PMNs only when used at the highest concentration studied (30 microM). Prostacyclin, 6-keto-PGF1 alpha and Iloprost (a carbacyclin analogue of prostacyclin) at concentrations up to 30 microM showed no significant inhibition of O2- in human PMNs stimulated either with FMLP or with zymosan. It is concluded that PGD2 and PGEs use a common basic mechanism for inhibition of the generation of O2- by PMNs activated with FMLP or zymosan. PGD2 is most generously furnished with these properties. In addition to this basic mechanism PGE2 and 6-keto-PGE1 abrogate the FMLP-induced response by occupation of formyl peptide receptor of PMNs. It is hypothesised that inhibition of the generation of O2- in PMNs and, possibly, in other cells by PGD2, PGE2 and by products of prostacyclin biotransformation might be responsible for their cytoprotective action in myocardial infarction, stroke, liver damage and peripheral vascular disease.